瑞典隆德大学Oskar Hansson团队研究了血液生物标志物在初级保健和二级保健中检测阿尔茨海默病的准确性。2024年7月28日出版的《美国医学会杂志》发表了这项成果。

阿尔茨海默病（AD）的准确血液测试可以简化AD的诊断工作和治疗。为了使用预先定义的生物标志物截断值，前瞻性评估初级和二级保健中临床上可用的AD血液测试，2020年2月至2024年1月，研究组对瑞典因认知症状正在接受临床评估的1213名患者进行了分析。

生物标志物截断值在一个独立队列中创建，适用于初级保健队列（N=307）和二级保健队列（N=300）；每个患者1份血浆样本作为每个队列单批的一部分进行分析。然后在初级保健队列（N=208）和二级保健队列（N=398）中对血液测试进行前瞻性评估；每个患者在初次采集2周内再送1份血浆样本进行分析。使用基于质谱血浆分析的血液测试来确定血浆磷酸化tau 217（p-tau217）与非p-tau217（以p-tau217的百分比表示）的比率，以及与淀粉样蛋白-β42和淀粉样蛋白-β40（Aβ42:Aβ40）结合的血浆比率（淀粉样蛋白概率得分2[APS2]）。主要结局是AD病理学（由异常的脑脊液Aβ42:Aβ40比值和P-Tau217确定）。第二个结果是临床AD。还计算了阳性预测值（PPV）、阴性预测值（NPV）、诊断准确性和曲线下面积（AUC）值。

参与者的平均年龄为74.2岁（SD，8.3岁），48%为女性，23%的人有主观认知下降，44%的人有轻度认知障碍，33%的人有痴呆症。在初级保健和二级保健评估中，50%的患者AD病理学确诊。当在初级保健队列中对血浆样本进行单批分析时，使用APS2时的AUC为0.97（95%CI，0.95-0.99），PPV为91%（95%CI，87%-96%），NPV为92%（95%CI，87%-96%）；在二级保健队列中，使用APS2时AUC为0.96（95%可信区间，0.94-0.98），PPV为88%（95%可信区间，83%-93%），NPV为87%（95%可信区间，82%-93%）。在初级保健队列中，当对血浆样本进行前瞻性分析（每周两次）时，使用APS2时的AUC为0.96（95%CI，0.94-0.98），PPV为88%（95%CI，81%-94%），NPV为90%（95%CI，84%-96%）；在二级保健队列中，使用APS2时的AUC为0.97（95%CI，0.95-0.98），PPV为91%（95%CI，87%-95%），NPV为91%（95%CI，87%-95%）。

这4组的诊断准确性很高（范围为88%-92%）。初级保健医生在临床检查、认知测试后识别临床AD的诊断准确率为61%（95%CI，53%-69%），使用APS2进行计算机断层扫描的诊断准确率为91%（95%CI，86%-96%）。痴呆症专家的诊断准确率为73%（95%CI，68%-79%），而使用APS2诊断准确率为91%（95%CI，88%-95%）。在整个人群中，使用APS2的诊断准确性（90%[95%CI，88%-92%]）与仅使用P-Tau217百分比的诊断准确性（90%[95%CI，88%-91%]）没有区别。

研究结果表明，APS2和单独P-Tau217的百分比，在使用预先定义的截断值在初级和二级保健中有认知症状的个体中，识别AD具有很高的诊断准确性。未来的研究应评估对这些生物标志物使用血液测试如何影响临床保健。

附：英文原文

Title: Blood Biomarkers to Detect Alzheimer Disease in Primary Care and Secondary Care

Author: Sebastian Palmqvist, Pontus Tideman, Niklas Mattsson-Carlgren, Suzanne E. Schindler, Ruben Smith, Rik Ossenkoppele, Susanna Calling, Tim West, Mark Monane, Philip B. Verghese, Joel B. Braunstein, Kaj Blennow, Shorena Janelidze, Erik Stomrud, Gemma Salvadó, Oskar Hansson

Issue&Volume: 2024-07-28

Abstract:

Importance  An accurate blood test for Alzheimer disease (AD) could streamline the diagnostic workup and treatment of AD.

Objective  To prospectively evaluate a clinically available AD blood test in primary care and secondary care using predefined biomarker cutoff values.

Design, Setting, and Participants  There were 1213 patients undergoing clinical evaluation due to cognitive symptoms who were examined between February 2020 and January 2024 in Sweden. The biomarker cutoff values had been established in an independent cohort and were applied to a primary care cohort (n=307) and a secondary care cohort (n=300); 1 plasma sample per patient was analyzed as part of a single batch for each cohort. The blood test was then evaluated prospectively in the primary care cohort (n=208) and in the secondary care cohort (n=398); 1 plasma sample per patient was sent for analysis within 2 weeks of collection.

Exposure  Blood tests based on plasma analyses by mass spectrometry to determine the ratio of plasma phosphorylated tau 217 (p-tau217) to non–p-tau217 (expressed as percentage of p-tau217) alone and when combined with the amyloid-β 42 and amyloid-β 40 (Aβ42:Aβ40) plasma ratio (the amyloid probability score 2 [APS2]).

Main Outcomes and Measures  The primary outcome was AD pathology (determined by abnormal cerebrospinal fluid Aβ42:Aβ40 ratio and p-tau217). The secondary outcome was clinical AD. The positive predictive value (PPV), negative predictive value (NPV), diagnostic accuracy, and area under the curve (AUC) values were calculated.

Results  The mean age was 74.2 years (SD, 8.3 years), 48% were women, 23% had subjective cognitive decline, 44% had mild cognitive impairment, and 33% had dementia. In both the primary care and secondary care assessments, 50% of patients had AD pathology. When the plasma samples were analyzed in a single batch in the primary care cohort, the AUC was 0.97 (95% CI, 0.95-0.99) when the APS2 was used, the PPV was 91% (95% CI, 87%-96%), and the NPV was 92% (95% CI, 87%-96%); in the secondary care cohort, the AUC was 0.96 (95% CI, 0.94-0.98) when the APS2 was used, the PPV was 88% (95% CI, 83%-93%), and the NPV was 87% (95% CI, 82%-93%). When the plasma samples were analyzed prospectively (biweekly) in the primary care cohort, the AUC was 0.96 (95% CI, 0.94-0.98) when the APS2 was used, the PPV was 88% (95% CI, 81%-94%), and the NPV was 90% (95% CI, 84%-96%); in the secondary care cohort, the AUC was 0.97 (95% CI, 0.95-0.98) when the APS2 was used, the PPV was 91% (95% CI, 87%-95%), and the NPV was 91% (95% CI, 87%-95%). The diagnostic accuracy was high in the 4 cohorts (range, 88%-92%). Primary care physicians had a diagnostic accuracy of 61% (95% CI, 53%-69%) for identifying clinical AD after clinical examination, cognitive testing, and a computed tomographic scan vs 91% (95% CI, 86%-96%) using the APS2. Dementia specialists had a diagnostic accuracy of 73% (95% CI, 68%-79%) vs 91% (95% CI, 88%-95%) using the APS2. In the overall population, the diagnostic accuracy using the APS2 (90% [95% CI, 88%-92%]) was not different from the diagnostic accuracy using the percentage of p-tau217 alone (90% [95% CI, 88%-91%]).

Conclusions and Relevance  The APS2 and percentage of p-tau217 alone had high diagnostic accuracy for identifying AD among individuals with cognitive symptoms in primary and secondary care using predefined cutoff values. Future studies should evaluate how the use of blood tests for these biomarkers influences clinical care.

DOI: 10.1001/jama.2024.13855

Source: https://jamanetwork.com/journals/jama/fullarticle/2821669